Seminars in Cancer Biology 69 (2021) 391–398

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Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Targeted delivery of miRNA based therapeuticals in the clinical

management of Glioblastoma Multiforme
Faheem Hyder Pottoo a, *, Md. Noushad Javed b, c, **, Jawad Ur Rahman d, Tareq Abu-Izneid e,
Firdos Alam Khan f, *
a
Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam 31441, Saudi Arabia
b
Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New-Delhi, India
c
School of Pharmaceutical Sciences, Apeejay Stya University, Gurugram, Haryana, India
d
Department of Microbiology, College of Medicine, Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam, 31441, Saudi Arabia
e
Pharmaceutical Sciences, College of Pharmacy, Al Ain University, Al Ain, Abu Dhabi, United Arab Emirates
f
Department of Stem Cell Research, Institute for Research and Medical consultations (IRMC), Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam,
31441, Saudi Arabia

A R T I C L E I N F O A B S T R A C T

Keywords: Glioblastoma multiforme (GBM) is the most aggressive (WHO grade IV) form of diffuse glioma endowed with
Glioblastoma tremendous invasive capacity. The availability of narrow therapeutic choices for GBM management adds to the
miRNA irony, even the post-treatment median survival time is roughly around 14-16 months. Gene mutations seem to be
nanoparticles
cardinal to GBM formation, owing to involvement of amplified and mutated receptor tyrosine kinase (RTK)-
signaling pathways
BBB
encoding genes, leading to dysregulation of growth factor signaling pathways. Of-late, the role of different
BBTB microRNAs (miRNAs) in progression and proliferation of GBM was realized, which lead to their burgeon po­
nanomedicine tential applications for diagnostic and therapeutic purposes. miRNA signatures are intricately linked with onset
receptor tyrosine kinase and progression of GBM. Although, progression of GBM causes significant changes in the BBB to form BBTB, but
still efficient passage of cancer therapeutics, including antibodies and miRNAs are prevented, leading to low
bioavailability. Recent developments in the nanomedicine field provide novel approaches to manage GBM via
efficient and brain targeted delivery of miRNAs either alone or as part of cytotoxic pharmaceutical composition,
thereby modulating cell signaling in well predicted manner to promise positive therapeutic outcomes.

1. Introduction schwannomas, meningiomas and medulloblastomas. Glioma can be

Glioma is the commonest destructive form of primary brain tumors
affecting 3.19/100000 person in USA alone. Glioma is more prevalent in
caucasians than afro-american, african-asian and american –Indians,
with males being the most affected one. This collection of malignant
tumors of central nervous system actually protrudes from the glial cells
(which basically surround neurons for support and insulation within the
brain). Briefly, as per histology, glioma can be classified into high-grade
glioma like anaplastic astrocytoma IDH mutant/IDH wild type, mutant/
IDH wild type, glioblastoma IDH and midline diffuses Glioma H3
K272M-mutant or low-grade gliomas like astrocytoma, oligoden­
droglioma mixed glioma (mixurre of astrocyte and oligodendrocytes).
Other tumors of glial origin are ependymomas, CNS lymphomas,
further classified on the basis of location, and characteristic features of
differentiation or anaplasia. Based on the presence or absence of
anaplasia the malignant glioma is classified into subtype I-IV according
to WHO standards [1]. In brief; WHO reclassified the tumors of CNS and
more particularly brain gliomas into grades I-IV by integrating histo­
pathological and molecular genetic markers (Isocitrate dehydrogense
Wildtype /mutation & 1p/19q codeleted /non-codeleted). Due to inva­
siveness as well as aggressiveness; this undifferentiated Glioblastoma
multiforme has been designated as Grade IV tumor by WHO [2]. The
current therapeutic regimen for GBM includes safe removal of the lesion
along with chemotherapy with temozolomide (TMZ) and radiotherapy,
but still limited clinical success had been met [3–5].
Epigenetics regulate both formation and suppression of tumors by

* Corresponding authors.
** Corresponding author at: School of Pharmaceutical Sciences, Apeejay Stya University, Gurugram, Haryana, India.
E-mail addresses: fhpottoo@iau.edu.sa, fahihyder@gmail.com (F.H. Pottoo), rxnoushad@gmail.com (Md.N. Javed), fakhan@iau.edu.sa (F.A. Khan).

https://doi.org/10.1016/j.semcancer.2020.04.001
Received 14 November 2019; Received in revised form 7 April 2020; Accepted 8 April 2020
Available online 14 April 2020
1044-579X/© 2020 Elsevier Ltd. All rights reserved.

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F.H. Pottoo et al.
regulating different types of genetic modifications such as, cytosine
methylation at CpG doublets, acetylation, methylation, & phosphory­
lation of histone proteins or by change in the three dimensional chro­
matin conformation [3,6]. miRNAs which are non-coding RNAs of 22bp
size mediate expression of several genes both at mRNA and protein level
[7–9]. miRNA signatures are intricately linked with onset and progres­
sion of GBM, the upregulated miRNAs are miR-10a, miR-22, miR-34a,
miR-129-3p, miR-132, miR-146b-5p, miR-149, miR-152, miR-155,
miR-195, miR-221, miR-222, miR-296-3p, miR-671-5p, while
down-regulated are let-7b, miR-19a, miR-19b, miR-20a, miR-767-5p,
miR-106a, miR-181a, -301b, miR-505 [10,11]. The miRNAs have
gained immense interest since their evidence of linkage between altered
expression levels and tumors had been reported [12,13]. In GBM, major
molecular targets of miRNAs includes PTEN, MDM2 (Mouse double
minute 2 homolog), TSC1 (tuberous sclerosis complex-1), POLD2 (DNA
Polymerase Delta 2,), TGFβ-RII (transforming growth factor-β receptor
II), CTGF (connective tissue growth factor) and CAMTA1 (Calmodulin
Binding Transcription Activator 1) [14]. The GBM correlates with
elevated expression levels of ALDH1A3 (Aldehyde Dehydrogenase 1
Family Member A3). Hence, adaptation of approaches, such as miRNA
targeting drugs or biological macromolecules, would provide some
unique solutions to inhibit elevated expression of ALDH1 levels in GBM
and unravel development of potential therapeuticals [15,16]. It is also
quite important to confess the fact that even a single miRNA may
regulate multiple targets which would influence the formation, pro­
gression, proliferation and migration of GBM [17,18]. The expression
levels of some IDH mutations (prognostic), promoter methylation,
MGMT (O-methylguanine–DNA methyltransferase) and 1p/19q predic­
tive co-deletion, related biomarkers are extensively employed in the
clinical management of GBM [19].
2. miRNA Biogenesis
Briefly, biogenesis of miRNA starts with the transcription of primary
miRNA (> 1kbps) from the cellular DNA sequence, via RNA polymerase
II enzyme, in the nucleus of animal cells. Initially it resembles as a long
hairpin like double stranded RNA structures, comprising multiple
nucleotide segments required for its processing and maturation. In the
nuclear region, an endonuclease i.e. RNAse III Drosha, in association
with cofactor DiGeorge Syndrome Critical Region 8 (DGCR8); develops
into unique complex called microprocessor. This complex precisely cuts
the pri-miRNA and degradation it into a secondary product of ~65bps
pre-miRNA [20]. Such newly generated pre-miRNAs are then exported
into the cytoplasm via transportation complex comprising exportin 5
(EXP5), RAN, GTP and pre-miRNA [21,22]. As soon as the complex
crosses the nuclear membrane, the RNAse protein (Dicer) cleaves the
pre-miRNA into a ~22 bp miRNA creating a small Duplex miRNA with
the help of TAR RNA-binding protein (TRBP or PACT). Activated Dicer
as well as DGCR8 complex are believed to be auto-regulated in the nu­
cleus of the cells. The newly formed Duplex miRNA is laden on a
particular AGO protein (1 of a 4 types), forming a precursor-RNA
Induced silencing complex (pre-RISC). Subsequently, after degradation
of one strand of the double helix in pre-RISC it immediately modifies to
become mature RISC [18,20,23]. A number of studies have shown
regulation of hundreds of targets via a single miRNA including glioma
formation and its proliferation. About 1% of miRNAs (Mirtrons) are
produced via non-canonical mechanism in which need of Drosha/Dgcr8,
in the nucleus of a cell, is avoided. Additionally these types of miRNA are
actually encoded by the excited introns of the primary mRNA transcript
which are cleaved by action of spliceosomes as well as endonucleases as
intron lariat. The intron lariat is debranched or linearized by DBR1
enzyme (in Humans) followed by transportation into cytoplasm by ac­
tion of XPO5 enzyme for DICER cleavage and subsequent maturation
into miRNA. The miRNA interacts with mRNA either at its 3’ UTR region
to suppress or at 5’UTR region to favor expression levels [20,24].
392
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Seminars in Cancer Biology 69 (2021) 391–398
3. Interaction of miRNAs with signaling pathways in
glioblastoma multiforme
Mutation or amplification of Genes had been commonly reported
among p53, receptor tyrosine kinase (RTK)/RAS/PI3K as well as in
retinoblastoma tumor suppressor signaling pathways [25]. The dysre­
gulated receptor tyrosine kinase (RTK, including, MET, EGFR, PDGFRα,
etc.) signaling pathways are correlated for their critical role in pro­
gression of various cancers including gliomas, but have now become
prominent characteristics of GBM cases [26–28]. A number of primary
GBM based studies have established overexpressed EGFR (epidermal
growth factor receptor) presence in more than 60% of cases [29,30]. The
EGFR signaling pathways from the plasma membrane includes: PI3K/­
protein kinase B (PKB/AKT) pathway, protein kinase C (PKC) pathway,
RAS/mitogen activated protein kinase (MAPK)/extracellular signal­
–regulated kinase (ERK) pathway and Janus Kinase (JAK)/STAT
pathway [31]. miRNAs in accordance with their capacity to modulate
signaling pathways ensure homeostasis, metastasis and fibrosis [32], e.g
miR-29a downregulates PTEN, EphB3 and SOX4 to mediate activation of
complicated post-transcriptional program for promoting the prolifera­
tion and invasion of GBM [33]. miR-34a & miR-451 inhibit signaling
through AKT and thereby exhibit tumor suppressor effects in GBM [34,
35]. miR-7 inhibits EGFR and Akt activity thereby reduces GBM inva­
siveness [36]. Thus, miRNAs exhibit potential role in the clinical man­
agement of GBM w.r.t modulation of diverse signaling pathways
(Fig. 1).
3.1. RAS/mitogen activated protein kinase (MAPK)/extracellular
signal–regulated kinase (ERK) pathway
EGFR recruits the SH2 domain bearing protein-GRB2. The GRB2 is
associated with RAS GEF SOS as a preformed complex, to facilitate
activation of RAS. This activated RAS drives the RAF-MAPK/ERK kinase
(MEK)-ERK1/2 signaling cascade. Subsequently, activation of ERK1/2
(critical regulator of proliferation, survival and metabolism) phosphor­
ylates downstream substrates, which get translocated into the nucleus to
modulate various proteins and transcription factors. In tumors with
mutated or deleted NF1, the activation of RAS was reported which was
measured in terms of p-ERK and p-MEK [31,37,38].
3.2. PI3K/protein kinase B (PKB/AKT) pathway
Activation of EGFR induces phosphoinositide 3-kinase (PI3K) to
synthesize phosphatidylinositol (3,4,5) trisphosphates (PIP3) from
Phosphatidylinositol 4,5-bisphosphate (PIP2). At the membrane site,
Akt bound to PIP3, is phosphorylated at Thr308PDK1 by PDK1, leading
to its partial activation. Subsequently, PDK2 phosphorylates Akt at
Ser473 to induce full activity [39]. Such duo-phosphorylated Akt in­
duces the cytoplasmic events like phosphorylation of TSC2. Activated
TCS2 relieves repressive effects on Rheb causing cell proliferation, in­
hibition of apoptosis and downstream activation of mTOR [40]. In
contrary, tumor suppressor phosphatase and tensin homolog (PTEN)
dephosphorylates PIP3 and inhibits enzymatic activities of Akt (mutated
in GBM). Recently, it was also established that before the amplification
of EGFR, there is loss of PTEN containing 10q chromosome [31]. GBM
tumor and cell lines based genomic analysis revealed mutation in
RTK/PTEN/PI3K pathway by confirming elevated phospho-AKT levels
[41,42].
3.3. The JAK/STAT pathway
Upon activation of EGFR, intracellular JAKs phosphorylate each
other, which inturn phosphorylates STATs, leading to STAT dimeriza­
tion and their translocation into the nucleus [43], followed by their
binding at enhancer sequences located in 3’ or 5’ position of dimer or
complex oligomer to halt transcriptional activities of target gene [31,44,
F.H. Pottoo et al.
Fig. 1. Modulation of EGFR signaling pathways in gliobalstoma multiforme with miRNAs.
45].In GBM, although STAT-3 exhibit relatively lower frequency of
mutation however localized (microenvironment) presence of IL-6 leads
to its aberrant activation [46].
3.4. The Phospholipase C (PLC)/PKC pathway
Activated EGFR recruits and activates PLC, which catalytically
cleavages PIP2 into inositol 1,4,5-trisphosphate (IP3) and di-acyl glyc­
erol (DAG). Active PLC also stimulates PKC which inturn triggers
numerous regulatory molecules to affect angiogenesis, infiltration,
proliferation and survival events in tumors [31]. The downstream ef­
fectors of PKC isoenzymes are cellular cycle regulators- p53 and p21,
regulators of cellular growth & proliferation -RAS-RAF1 and glycogen
synthase kinase 3 (GSK3), cell motility regulators-integrins, cell survival
regulators- BCL2 and BAD, as well as inflammation regulator NFκB [47,
48].
4. Rationalizing nanoparticles for miRNA delivery in
glioblastoma multifome
4.1. The blood-brain barrier and challenges to drug delivery
Tangled transmembrane complex of non-fenestrated endothelial
cells, microglia, pericytes, astrocytes and basement membrane assem­
bled with structural proteins such as collagen, laminin, junctional
adhesion molecule-1, occludin, claudins, and cytoplasmic proteins
(zonula occludens-1 & 2) form extensive tight junctions of protective
blood-brain barrier (BBB) surrounding the brain. Primary role of BBB is
to strictly deny paracellular entry, majorly of systemically circulating
molecules, more prominently hydrophilic agents, owing to their exog­
enous origin [49]. The process of piocytosis which is some non-specific,
non-saturable, non-carrier-mediated vesicular transportation however
may felicitate vesicular uptake of bulk fluids and their solute compo­
nents within the cells, from the site of their microenvironment. The
passage of these hydrophilic solutes is usually energy-independent
processes so their level in brains are insignificant unless transported as
substrates of any transporters (such as GLUT 1,3,4,5,6 and 8: glucose
transporters for hydrophilic glucose molecules) [50]. In order to exploit
this; the glucose-RGD (Glu-RGD) derivative was synthesized as ligand
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Seminars in Cancer Biology 69 (2021) 391–398
which favored selective targeting and accumulation of paclitaxel (PTX)
liposomes in glioma cells (up-to 4.72-fold higher uptake than pure drug)
[51].
In parallel to this, SLC7A5-13, and SLC7A15 [L-type amino acid
transporters (LATs)] and SLC7A1-4 and SLC7A14 [cationic amino acid
transporters (CATs)] which belong to solute carrier family 7 (SLC7) as
well as heteromeric amino acid transporter (HAT) such as LAT1
(SLC7A5); exhibit unusual high expression levels during cancer pro­
gression, and were thus visualized as channels delivering essential
amino acids into the tumor cells via some unknown cancer-associated
reprogrammed metabolic networks, thereby promoting normal cancer
growth into high-grade tumors with metastasis [52,53]. The, overex­
pressed multi-drug transporters like P-glycoprotein at brain capillary
endothelial cells and astrocytic end-feet, further complicate the situation
by ensuring expulsion of exogenous molecules/drugs out of brain i.e
reduction of drug bioavailability. Hence, approaches for combining
chemo-therapeuticals with inhibitory substrates of such efflux confer­
ring transporters are critical to reduce dose of drugs, increase the
bioavailability as well as to encounter multidrug resistance incidents of
GBM [54].
Apart from the protective role as well as secretion of both barrier-
promoting as well as barrier-disrupting factors, BBB, by virtue of its
paracrine interaction with astrocytes, pericytes and ECs, enables inter­
linked network of neuronal signals. The paracrine interaction of BBB
with astrocytes co-regulates the blood flow. While astrocytes also
regulate matrix metalloproteinase for the purpose of breakdown of the
basement membrane during neuronal inflammation, so that entry of
immune cells would be felicitated inside the brain [55]. Similarly,
functions of pericytes which enwrap blood microvessels cells, is to
maintain BBB homeostasis, regeneration of stroma, process of angio­
genesis and neo-vascularization, regulation of antigen presenting cells
during brain infections, differentiation of neural stem cell attributes, as
well as EC proliferation [56]. In addition, lecticans, tenascins, hyal­
uronic acid, proteoglicans as well as hyaluronan constitutes extracel­
lular matrix (ECM) which serves as base component of BBB structures,
and also interacts with other matrix proteins such as laminin and
endothelial integrin, to ensure establishment of harbored endothelium
networks as well as regulation of paracellular diffusion [56,57]
F.H. Pottoo et al.
4.2. Impact of glioblastoma multifome progression on the blood-brain
barrier
In the progression of cancerous states, including GBM, the changes in
morphology, permeability and functionality of BBB, render it more
suitable terminology i.e blood-brain tumor barrier (BBTB) [58]. During
initial (1st phase) progression of cancer, capillaries maintain continuous
and non-fenestrated i.e. integrity, morphology and functionality of BBB
is not affected significantly. But, as the cancer progress into 2nd growth
phase, cancer cells start invading surrounding tissues, grow-up into
around few (2-3) mm of volume, followed by alteration in permeability
of the BBB due to neovascularization. In this angiogenesis mediated
neovasculature formation, newly formed capillaries (12 nm size) which
are of continuous and fenestrated morphology, start allowing very se­
lective and spherical nutrient molecules up-to 12 nm to cross through
this newly formed barrier i.e., BBTB. While, in 3rd or final stage; char­
acteristic features such as enlargement of capillary fenestration size
usually upto 48 nm, reduction in micro-vessel basement membrane
thickness, loss of junctional proteins, increased inter-endothelial gaps
up-to 1 μm, taunts the full integrity of BBTB [59]. The peptides based
biomolecules are being released from tumor cells of CNS into blood
serum which can be exploited as affluent source of potentially predictive
cancer specific biomarkers. CTCs, ctDNA and MVs have been sampled
from different biofluids in GBM patients [60,61].
4.3. Nanotechnology enabled miRNA targeted delivery in glioblastoma
multifome
The complexity of CNS and presence of physiological barriers pos­
sesses major scientific challenges, in conventional delivery approaches
for newly synthesized drugs or hydrophilic molecules or phytocon­
stituents in neurological disorders and cancers, such as glioma (GBM)
[62–65]. Furthermore, In contrast to the neuronal delivery of synthetic
chemical analogues, miRNA-based therapeuticals, bear additional
challenges due to their susceptibility towards enzyme and PH mediated
degradation even before reaching the target sites [66]. Hence in lieu of
above, it would be judicious to develop an efficient and biocompatible
carrier system which would felicitate entry of nucleic acid loads to
specific areas within the brain, without being subjected to degradation.
The nanotechnology fabricated carriers e.g polymeric systems, lipid
based carriers, liposomes and metallic nanoparticles hold the capacity
and efficiency to deliver the miRNA based loads [67–69]. Inaddition, the
surface of metallic nanoparticles, such as spherical silver and gold NPs,
have been attributed to their catalytic properties; hence exploited for
functionalization purposes of peptide analogues [70].The integration of
nanotechnology to deliver rationalized pharmaceutical compositions, is
the most favorable approach which significantly reduces the burden of
drug regimen by reducing the course of treatment, coupled with
improved potential therapeutic outcomes and minimal side effects
[71–73]. The efficient delivery of tumor suppressor micro­
RNA–conjugated systems using nanotechnological processed carriers in
brain is very promising field. The miRNA nanoparticles based drug de­
livery systems therefore provides new means to rationalize selection of
appropriate approaches to enhance overall permeability of loaded bio­
molecules or drugs, with enhanced retention impacts i.e. by exploiting
nanoparticulated drug delivery leading into enhanced permeation and
retention (EPR) of loaded miRNA preferentially within the cancer
affected regions in brain for the effective clinical management of GBM
[74–76]. Therefore, various novel drug delivery approaches for miRNA
delivery in cases of GBM had been developed in the recent past.
In order to efficiently knock down miR-21 (oncomir) expression in
GBM, anti-miR-21 LNA loaded Multi-valentfolate (FA)-conjugated 3 W J
RNP were injected into glioblastoma cells in vitro to induce rescue of
tumor suppressors; PTEN and PDCD4 culminating into apoptosis [77].
The delivery of miR-21 antisense oligonucleotide (anti-miR-21) via lipid
and polymer constituting unique single hybrid systems; lipid-polymer
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Seminars in Cancer Biology 69 (2021) 391–398
nanoparticles (LPNs), efficiently targeted glioblastomas [78].
PLGA-Nanoparticle encapsulated antisense miR-21 delivered prior to
TMZ treatment of cells, significantly brought down the number of viable
cells (p < 0.001). Similarly cell cycle arrest at G2/M phase increased
(1.6-fold) upon treatment with TMZ in U87 MG cells [79]. The delivery
of anti-miR-21 oligo-nucleotides via Chlorotoxin (CTX)-coupled SNALP
promoted silencing of miR-21, elevation of PTEN and PDCD4, activation
of caspase 3/7, culminating in reduced tumor size/ proliferation,
apoptosis and improvement of animal survival [80]. Nadiya M Teplyuk
et al., 2016 applied convection-enhanced delivery (CED) to continu­
ously deliver anti-miR-10b-containing nanoparticles for two weeks, via
intracranial osmotic pumps, significant reduction in intracranial GBM
progression and cell proliferation with increase in apoptosis was
observed. All of these properties were evident from decreased staining
for proliferation markers PCNA and KI67 (cleaved caspase 3 staining)
[81].
Polymeric nanogels (NGs)-miR-34a nano-polyplexes upregulated
miR-34a while downregulating its target oncogenes like c-MET, CDK6,
Notch1 and Bcl-2 in Human U-87 MG GBM cells resulting in inhibition of
proliferation/migration of cells in vitro, and also tumor suppression in
GBM-bearing SCID mice [82]. Dendritic polyglycerolamine (dPG-NH2)–
miR-34a polyplex reduced expression of oncogenes like C-MET, CDK6,
Notch1 and BCL-2 in U-87 MG human cells leading to inhibition of cell
cycle progression, proliferation and migration of GBM cells in vitro, and
reduction of tumor growth in GBM inoculated SCID mice [83]. CXCR4
receptor-stimulated lipoprotein-like nanoparticle (SLNP) loaded with
microRNA-34a in the core, reduced expression of Y-box 2 (sex-de­
termining region) and Notch1, thereby Inhibited GICs stemness and
chemoresistance and significantly prolonged the survival of GICs-bear­
ing mice [84]. An evident increment in apoptosis and decrement in
proliferation was observed when GBM tissue slices were treated with
nanoparticle loaded with miR-29b, resulting in reduction in expression
of COL1A2, COL3A1, COL4A1, ELN, ITGA11, MMP24, and SPARC, to
mediate an anticancer effect [85].
In gliomas, miR221 is liked with invasiveness and temozolomide
resistance. The, delivery of temozolomide (TMZ) in association of anti-
miR221 PNA, loaded on mesoporous silica nanoparticles (MSNPs),
induced apoptosis in TMZ resistant T98 G cells [75]. The combination of
anti-miR-21 oligo-nucleotides via Chlorotoxin (CTX)-coupled SNALP
with Sunitinib (a tyrosine kinase inhibitor) decreased tumor cell pro­
liferation & enhanced apoptosis in C57BL/6 mice [80]. The delivery of
5-FU and antisense miR-21 constituting synergistic pharmaceutical
compositions via PAMAM based carriers exhibited prominent anti­
proliferative effect in human glioma U251 cells [86]. In association with
TMZ, both antagomiR-21 and antagomiR-10b, delivered into U87MG
and Ln229 GBM cells via PLGA based and cRGD-targeting nano-carriers,
not only efficiently arrested cell cycle at G2/M phase but also sensitized
cells, even to low concentrations of TMZ [87]. The, combo-delivery of
miR-148a and miR-296-5p containing pharmaceutical compositions not
only inhibited stem cell phenotype of human GBM cells in vitro but also
increased long-term survival in athymic nude NCR Nu/Nu and response
to γ radiation therapy [88]. Among metallic nanoparticles, Iron oxide
owing to its magnetic properties is being exploited for external magnet
controlled localized release of drugs as well as hyperthermia mediated
apoptosis of tumors, including GBM [89,90]. While, silver and gold
nanoparticles, owing to their anti-infectious properties as well as unique
SPR (Surface Plasmon Resonance) mediated analytical signal amplifi­
cations, are exploited not only for their restricted use as drug carriers but
also for diagnosis of state of GBM [91–93]. Hence, unique single hybrid
system of both gold and iron oxide nanoparticles (GIONs) was developed
with functionalized β-cyclodextrin-chitosan (CD-CS) hybrid polymer
and PEG-T7 peptide, for co-delivery of miR-100 and antimiR-21, the
delivery of which in association of TMZ lead into synergistically
enhanced anticancer potentials in U87-MG GBM cell-derived orthotopic
xenograft models in mice [94]. Hence with inspiration of all related
studies; nanotechnology platform enabled delivery of RNA interference
F.H. Pottoo et al. Seminars in Cancer Biology 69 (2021) 391–398

therapeuticals assures promising therapeutic response to efficiently 6. Conclusion

combat gliomas (Tables 1 and 2).
5. Future prospects
The recent promising discoveries and evidences on critical role of
miRNAs in the formation & progression of glioma, enable some of them
to emerge as exclusive clinical hallmarks in diagnosis, prognosis as well
as novel agents in mitigation of glioblastoma multiforme (GBM). Sub­
sequently, with the progression of GBM; the integrity of BBB is
compromised in a way that these miRNAs appeared to be released in a
systemic circulation, which could be exploited for early diagnosis &
identification of different stages of giloma. Advanced analytical tech­
niques like northern blotting, qRT-PCR, microarrays and NGS needs to
be standardized, validated and integrated to generate and process the
complex raw data in establishing definitive clinical decisions. Further­
more, additional techniques such as enzymatic amplification may be
required to identify those miRNAs which are specific hallmarks in GBM
but give poor signaling. The unique SPR attributes of metallic nano­
particles would favor adequate amplification of these detection signals.
In the past assessment of promising role of nanotechnology based ma­
terials and processes with synthetic and spiked- samples validated as
proof-of-principle. But the absence of internationally recognized regu­
latory procedures as well as stringent quality control strategies limits the
clinical translation of these strategies. The above mentioned unmet is­
sues and challenges needs to be addressed in a very judicious and sci­
entific way which would regulate the integration of nanotechnological
techniques for site specific delivery of miRNAs in clinical settings.
Herein, we reviewed the biological nature of GBM tumors, the
devastating outcome for patients, the failure of chemo and radio therapy
and recent progress in establishing the role of miRNAs as diagnostic
markers as well as therapeutic agents (alone or in combination with
chemotherapeutic molecules) in mitigation of GBM. The deeper under­
standing of miRNAs and their capacity to modulate signaling pathways,
which govern tumorigenicity opens new avenues for improving the life
expectancy and QoL of GBM patients. But these miRNAs exhibit low
stability, solubility and achieve non-site selective targeting, which
paved way for nanotechnological based novel delivery approaches. Over
the last few years, progress and advancement in nanotechnology-driven
strategies to fabricate novel material/s for targeted drug delivery of
biological macromolecules (such as peptides, RNA, miRNAs etc) and
chemotherapeuticals enabled by the state of the art, controlled, func­
tionalized and target centric modus operandi, accomplishes specific
functions to cater the need required for. Different types of nanoparticles,
such as silver nanoparticles, colloidal gold, silica nanoparticles, lipo­
some, polymeric carriers, bioinspired systems, niosomes, limicubes,
NLC, SLN etc, have been rationalized for optimal benefit in different
pathological states including neuronal cancers. These delivery systems
not only protect miRNAs from degradation by nucleases but also in­
creases their half-life in the blood or serum. Inaddition, numerous
clinical trials reported combination therapies, likely be the most prom­
ising method for GBM treatment, and that nanotechnology allows
conjugation of miRNAs with anti-cancer drugs and that too with syn­
ergistic effects. Thus the successful treatment of GBM lies with the
effective nano-tech enabled delivery of miRNAs across the BBTB either
alone or in combinations.

Table 1
Nanotechnology enabled miRNA targeted delivery in Glioblastoma Multiforme (In vitro studies).
S. Nanoformulation/s type Rationale Model (animal/cell Outcomes References
NO line)

1. anti-miR-21 LNA loaded Multi- miR-21 knock down U87EGFRvIII or Gli36 Glioblastoma cell apoptosis [77]
valentfolate (FA)-conjugated 3 W J cells
RNP
2. Chlorotoxin (CTX)-coupled SNALP- miR-21 silencing, U87 human GBM and Decrease in tumor cell proliferation [95]
anti-miR-21 oligonucleotides PTEN and PDCD4 upregulation, caspase GL261 mouse glioma
3/7 activation cells
3. PACE-antimiR-21 nanoparticles & miR-21 suppression, PTEN upregulation U87 cells Apoptosis of human GBM cells [96]
PLA-HPG- antimiR-21
nanoparticles
4. PLGA nanoparticle encapsulated knock down endogenous miR-21 U87 MG, LN229, and Overexpression of the miR-21 target genes [79]
antisense miR-21 T98 G cells PTEN (by 67%) and caspase-3 (by 15%) upon
cotreatment with TMZ
5. 5-FU-Loaded PAMAM- antisense- Down-regulation of miR-21 Human glioma U251 as-miR-21 significantly improved the [86]
miR-21 cells cytotoxicity of 5-FU and dramatically increased
the apoptosis of U251 cells
6. LPNs loaded with pemetrexed and Co-delivery of anti-miR-21 & U87MG human improved accumulation of LPNs in the nucleus [78]
anti-miR-21 pemetrexed glioblastoma cells. of U87MG cells.
7. Nanoparticle loaded miR-29b marked decrease in proliferation and GBM tissue slices miR-29b inhibits the expression of COL1A2, [85]
significant increase in apoptosis after COL3A1, COL4A1, ELN, ITGA11, MMP24, and
miR-29b treatment SPARC, which mediate an anticancer effect.
8. NG-miR-34a nano-polyplexes upregulation of miR-34a and Human U-87 MG GBM Inhibition of cell proliferation and migration [82]
downregulation of its target oncogenes cells
like c-MET, CDK6, Notch1 and Bcl-2.
9. dPG-NH2–miR-34a polyplex lower expression of C-MET, CDK6, U-87 MG human cells Inhibition of cell cycle progression/ [83]
Notch1 and BCL-2 genes proliferation and migration of GBM cells
10. Cy5-MSNPs loaded with anti- down-regulation of miR221 temozolomide-resistant Effective induction of apoptosis (70.9% of [75]
miR221 PNA T98 G cell line. apoptotic cells)
11. cRGD-targeted PLGA nanoparticles Co-inhibition of miR-21 and miR-10b U87MG and Ln229 Improvement in sensitivity of these cells to [87]
encapsulating antagomiR-21 and increased cell cycle arrest at G2/M GBM cells lower concentrations of TMZ
antagomiR-10b phase upon TMZ treatment.
12. nano-miRs containing miR- Delivery of miR-148a + miR-296-5p GBM1A cells Inhibit the stem cell phenotype of human GBM [88]
148a + miR-296-5p cells in vitro

Abbreviations: Mesoporous silica nanoparticles (MSNPs; temozolomide (TMZ; peptide nucleic acids (PNAs; poly(amine-co-esters(PACE); poly(lactic acidand hyper­
branched polyglycerol (PLA-HPG); lipid-polymer hybrid nanoparticles (LPNs; Chlorotoxin (CTX; polymeric nanogels (NGs; Poly(lactic-co-glycolic acid(PLGA); Locked
Nucleic Acids (LNAs

395

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F.H. Pottoo et al. Seminars in Cancer Biology 69 (2021) 391–398

Table 2
Nanotechnology enabled miRNA targeted delivery in Glioblastoma Multiforme (In vivo studies).
S. Nanoformulation/s type Rationale Model (animal/cell line) Outcomes References
NO

1 ApoE coated PACE-antimiR -21 NPs & miR-21 inhibition, Male RNU rats (Convection-enhanced Increase in PTEN expression [96]
PLA-HPG- antimiR-21 nanoparticles delivery)
2. anti-miR-21 LNA loaded Multi-valentfolate PTEN and PDCD4 Athymic nu/nu outbred mice Tumor growth regression [77]
(FA)-conjugated 3 W J RNP upregulation
3. Chlorotoxin (CTX)-coupled SNALP-anti- miR-21 silencing Adult male C57BL/6 mice Decreased tumor cell proliferation & [80]
miR-21 oligonucleotides enhanced apoptosis in combination
with tyrosine kinase inhibitor;Sunitinib
4. Co-delivery of miR-148a and miR-296-5p Delivery of miR- athymic nude NCR Nu/Nu mice Long-term survival [88]
148a + miR-296-5p
5. Nanogels (NGs) -miR-34a nano-polyplexes GBM-bearing SCID mice Inhibited tumor growth [82]
6. cRGD-targeted and non-targeted PLGA Co-inhibition of miR-21 nude mice (nu/nu) Increase in cellular chemosensitivity [87]
nanoparticles encapsulating antagomiR-21 and miR-10b towards lower doses of TMZ
and antagomiR-10b
7. dPG-NH2–miR-34a polyplex Upregulaion of miR-34a SCID mice Inhibition of tumor growth [83]
8. FH38-miR34a-SLNPs Reduces sex-determining GICs-derived orthotopic mice models Inhibits GICs stemness and [84]
region Y-box 2 and chemoresistanceand significantly
Notch1 expression prolongs the survival of GICs-bearing
mice.
9. anti-miR-10b-containing nanoparticles Downregulation of miR- Intracranial human GSC-derived Attenuated growth and progression of [81]
10b (oncogenic miRNA) xenograft and murine GL261 allograft established intracranial GBM
models in athymic and
immunocompetent mice.
10. CD-CS coated GIONs co-loaded with miR- Downregulate miR-21 U87-MG GBM cell-derived orthotopic Significant increase in survival of mice [94]
100 and antimiR-21. surface and upregulate miR-100 xenograft models in mice. co-treated with T7-polyGIONs loaded
functionalization with PEG-T7 peptide with miR-100/antimiR-21 plus
using CD-adamantane host-guest systemic TMZ
chemistry.

Abbreviations: Chlorotoxin (CTX)-coupled (targeted) stable nucleic acid lipid particle (SNALP); glioma-initiating stem-like cells (GSC); gold-iron oxide nanoparticles
(polyGIONs); β-cyclodextrin-chitosan (CD-CS); cationic poly(amine-co-ester) (PACE); poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG).; peptide nucleic
acid (PNA); convection-enhanced delivery (CED)

Declaration of Competing Interest
The authors declare no conflict of interest
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